Annex 9 - WHO

1 439 World Health OrganizationWHO Technical Report Series, No. 937, 2006 Annex 9 Additional guidance for organizations performing in vivo bioequivalence studiesIntroduction1. Scope2. Glossary 3. Organization and management 4. Computer systems Hardware Software Data management 5. Archive facilities 6. Premises 7. Clinical phase 8. Clinical laboratory 9. Personnel 10. Quality assurance 11. Ethics Independent ethics committee Informed consent 12. Monitoring 13. Investigators 14. Receiving, storage and handling of investigational drug products15.

2 Case-report forms 16. Volunteers recruitment methods 17. Dietary considerations 18. Safety, adverse events and reporting of adverse events 19. Sample collection, storage and handling of biological material20. Bioanalytical data (laboratory phase) 21. Documentation 22. Pharmacokinectic and statistical calculations 23. Study report References Appendix 1 Examples of the list of standard operating procedures at the contract research 15:49 15:49:08440 IntroductionMultisource pharmaceutical products need to conform to the same stan-dards of quality, effi cacy and safety as required of the originator s (compara-tor) product. Specifi cally, the multisource product should be therapeutically equivalent and interchangeable with the comparator product.

3 Testing the bioequivalence between a product and a suitable comparator (pharmaceuti-cally equivalent or a pharmaceutical alternative) in a pharmacokinetic study with a limited number of subjects is one way of demonstrating therapeu-tic equivalence without having to perform a clinical trial involving many patients. In such a pharmacokinetic study any statement about the safety and effi cacy of the test product will be a prediction based on measurement of systemic concentrations, assuming that essentially similar plasma con-centrations of the drug will result in essentially similar concentrations at the site of action, and thus an essentially similar therapeutic outcome.

4 The bioequivalence study thus provides indirect evidence of the effi cacy and safety of a multisource drug product. Often this will be the only evidence that the product is safe and effi cacious. It is therefore crucial that the bio-equivalence study is performed in an appropriate manner. Several guidance documents stress the importance of on-site inspections to verify compli-ance with standards of good clinical practice (GCP) (1,2).The WHO prequalifi cation project was started in 2001 to assure that medici-nal products supplied for procurement meet WHO norms and standards with respect to quality, safety and effi cacy ( ). Spe-cifi cally it is a requirement that the submitted product dossier with all its nec-essary contents is assessed and found acceptable, and that the manufacturing sites of both the fi nished pharmaceutical product and of the active pharma-ceutical ingredient (API), are inspected and found to comply with WHO good manufacturing practices (GMP).

5 Because products submitted to the prequal-ifi cation project are usually multisource ( generic ) products, therapeutic equivalence is generally demonstrated by performing a bioequivalence study, for example in a contract resource organization (CRO). For prequalifi cation of such a product it is vital that, in addition to the above-mentioned require-ments, the CRO used by the sponsor to undertake the bioequivalence studies complies with WHO GCP and considers relevant elements from WHO good laboratory practice (GLP) and good practices for quality control laboratories to ensure integrity and traceability of data. Those involved in the conduct and analysis of bioequivalence studies on products to be submitted for prequali-fi cation therefore need to ensure that they comply with the above-mentioned WHO norms and standards to be prepared for any inspections by ScopeThe objective of this document is to provide guidance to organizations in-volved in the conduct and analysis of in vivo bioequivalence 15:49 15:49.

6 08441 bioequivalence studies should be performed in compliance with the general regulatory requirements and recommendations on good practices as speci-fi ed in the WHO bioequivalence guidelines (3), good clinical practices (1)and good laboratory practices (4) text below lists general recommendations for organizations (including CROs and laboratories) conducting bioequivalence studies and analysis of clinical trial samples. Recommendations for facilities and equipment are listed in the respective paragraphs. Recommended documents and records are listed in Appendix document provides information on: organization and management; study protocols; clinical phase of a study; bioanalytical phase of a study; pharmacokinetic and statistical analysis; and study present guidelines target organizations conducting bioequivalence stud-ies and highlight certain important aspects of the activities of such organiza-tions.

7 This document does not replace the above-mentioned GCP or GLP or good practices for quality control laboratories guidelines, which are more complete. It is, therefore, not a stand-alone document. For further guidance, see the guidelines for GCP for trials on pharmaceutical products (1).2. Glossary1 The defi nitions given below apply to the terms used in this guidance. They may have different meanings in other eventAny untoward medical occurrence in a clinical trial subject administered a pharmaceutical product; it does not necessarily have a causal relationship with the of a trialA systematic examination, carried out independently of those directly in-volved in the trial, to determine whether the conduct of a trial complies with the agreed protocol and whether the data reported are consistent with the records on site, whether data reported or recorded in the case-report forms (CRFs) are consonant with those found in hospital fi les and other original from Guidelines for WHO good clinical practice (GCP) for trials on pharmaceutical prod-ucts.

8 Geneva, World Health Organization, 1995 (WHO Technical Report Series, No. 850):97 15:49 15:49:08442bioequivalence testA test that determines the equivalence between the multisource product and the comparator product using in vivo and/or in vitro form (CRF)A document that is used to record data on each trial subject during the course of the trial, as defi ned by the protocol. The data should be collected by procedures which guarantee preservation, retention and retrieval of information and allow easy access for verifi cation, audit and productA pharmaceutical or other product (which may be a placebo) used as a reference in a clinical document, dated and signed by the investigator, institution and sponsor, that sets out any agreements on fi nancial matters and delegation/distribu-tion of responsibilities.

9 The protocol may also serve as a contract when it contains such information and is research organizationA scientifi c organization (commercial, academic or other) to which a spon-sor may transfer some of its tasks and obligations. Any such transfer should be defi ned in committeeAn independent body (a review board or a committee, institutional, regional or national), constituted of medical professionals and non-medical mem-bers, whose responsibility is to verify that the safety, integrity and human rights of the subjects participating in a particular trial are protected and to consider the general ethics of the trial, thereby providing public reassur-ance. Ethics committees should be constituted and operated so that their tasks can be executed free from bias and from any infl uence of those who are conducting the nal reportA comprehensive description of the trial after its completion including a description of experimental methods (including statistical methods) and materials, a presentation and evaluation of the results, statistical analysis and a critical, ethical, statistical and clinical clinical practice (GCP)A standard for clinical studies which encompasses the design, conduct, moni-toring, termination, audit, analysis, reporting and documentation of the 15:49 15.

10 49:09443and which ensures that the studies are scientifi cally and ethically sound and that the clinical properties of the pharmaceutical product (diagnostic, thera-peutic or prophylactic) under investigation are properly laboratory practice (GLP)A quality system concerned with the organizational process and the condi-tions under which nonclinical health and environmental safety studies are planned, performed, monitored, recorded, archived and consentA subject s voluntary confi rmation of willingness to participate in a particu-lar trial, and the documentation thereof. This consent should be sought only after all appropriate information has been given about the trial including an explanation of its status as research, its objectives, potential benefi ts, risks and inconveniences, alternative treatment that may be available, and of the subject s rights and responsibilities in accordance with the current revision of the Declaration of offi cially-conducted examination ( review of the conduct of the trial, including quality assurance, personnel involved, any delegation of authority and audit)